Understanding the nature of virus-specific immune responses that are able to control virus replication and prevent disease will be crucial to the strategic design and development of an AIDS vaccine. To characterize the evolution of these protective immune responses in macaques experimentally immunized with various SIV vaccines, we examined a variety of SIV-specific antibody parameters, including the antibody titer to native and recombinant envelope antigens, antibody reactive to conformational and linear envelope determinants, antibody avidity and antibody neutralization. Our results revealed a complex maturation of protective immune responses that is both time and virus strain dependent, identifying marked differences between SIV envelope-specific antibodies associated with protective and nonprotective immune responses. While an absolute correlation between one or more serological measurements and the production of a protective immune response to SIV by inoculation with a live attenuated virus vaccine was not identified we feel the results of these serological assays do allow certain definitive conclusions (1) The evolution of protective immunity in response to infection with attenuated virus strains is a lengthy process that requires a complex maturation of antibody responses. Based on the vaccine trials we studied, it would appear that an average of 6-8 months post inoculation is necessary to maximize the efficacy of protection. (2) This maturation process appears to require only low levels of viral antigen presentation as the attenuated strains at best established transient plasma viremias. (3) Once established, the protective immune responses are maintained for at least 2 years post inoculation, suggesting ongoing immune stimulation. (4) No single serological measurement provides an absolute correlate of protection. However, protective immune responses are associated with the presence of SIV envelope-specific serum antibodies that have a high titer to native envelope glycoproteins, that are high avidity, and that neutralize the virus in vitro. Furthermore, these results identify marked differences in the properties of SIV envelope-specific antibodies associated with protective and nonprotective responses, indicating candidate immune correlates of protection that can be useful prognostic indicators of AIDS vaccine trials.